Cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel

Abstract Lidocaine is known to inhibit the hyperpolarization-activated mixed cation current (Ih) in cardiac myocytes and neurons, as well in cells transfected with cloned Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels. However, the molecular mechanism of Ih inhibition by this dru...

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Autores principales:	Igor Putrenko, Raymond Yip, Stephan K. W. Schwarz, Eric A. Accili
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0be53e8d7de54a1891114f696cbf88a8
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spelling	oai:doaj.org-article:0be53e8d7de54a1891114f696cbf88a82021-12-02T16:06:32ZCation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel10.1038/s41598-017-01253-x2045-2322https://doaj.org/article/0be53e8d7de54a1891114f696cbf88a82017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01253-xhttps://doaj.org/toc/2045-2322Abstract Lidocaine is known to inhibit the hyperpolarization-activated mixed cation current (Ih) in cardiac myocytes and neurons, as well in cells transfected with cloned Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels. However, the molecular mechanism of Ih inhibition by this drug has been limitedly explored. Here, we show that inhibition of Ih by lidocaine, recorded from Chinese hamster ovary (CHO) cells expressing the HCN1 channel, reached a steady state within one minute and was reversible. Lidocaine inhibition of Ih was greater at less negative voltages and smaller current amplitudes whereas the voltage-dependence of Ih activation was unchanged. Lidocaine inhibition of Ih measured at −130 mV (a voltage at which Ih is fully activated) was reduced, and Ih amplitude was increased, when the concentration of extracellular potassium was raised to 60 mM from 5.4 mM. By contrast, neither Ih inhibition by the drug nor Ih amplitude at +30 mV (following a test voltage-pulse to −130 mV) were affected by this rise in extracellular potassium. Together, these data indicate that lidocaine inhibition of Ih involves a mechanism which is antagonized by hyperpolarizing voltages and current flow.Igor PutrenkoRaymond YipStephan K. W. SchwarzEric A. AcciliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Igor Putrenko Raymond Yip Stephan K. W. Schwarz Eric A. Accili Cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel
description	Abstract Lidocaine is known to inhibit the hyperpolarization-activated mixed cation current (Ih) in cardiac myocytes and neurons, as well in cells transfected with cloned Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels. However, the molecular mechanism of Ih inhibition by this drug has been limitedly explored. Here, we show that inhibition of Ih by lidocaine, recorded from Chinese hamster ovary (CHO) cells expressing the HCN1 channel, reached a steady state within one minute and was reversible. Lidocaine inhibition of Ih was greater at less negative voltages and smaller current amplitudes whereas the voltage-dependence of Ih activation was unchanged. Lidocaine inhibition of Ih measured at −130 mV (a voltage at which Ih is fully activated) was reduced, and Ih amplitude was increased, when the concentration of extracellular potassium was raised to 60 mM from 5.4 mM. By contrast, neither Ih inhibition by the drug nor Ih amplitude at +30 mV (following a test voltage-pulse to −130 mV) were affected by this rise in extracellular potassium. Together, these data indicate that lidocaine inhibition of Ih involves a mechanism which is antagonized by hyperpolarizing voltages and current flow.
format	article
author	Igor Putrenko Raymond Yip Stephan K. W. Schwarz Eric A. Accili
author_facet	Igor Putrenko Raymond Yip Stephan K. W. Schwarz Eric A. Accili
author_sort	Igor Putrenko
title	Cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel
title_short	Cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel
title_full	Cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel
title_fullStr	Cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel
title_full_unstemmed	Cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel
title_sort	cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated hcn1 channel
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0be53e8d7de54a1891114f696cbf88a8
work_keys_str_mv	AT igorputrenko cationandvoltagedependenceoflidocaineinhibitionofthehyperpolarizationactivatedcyclicnucleotidegatedhcn1channel AT raymondyip cationandvoltagedependenceoflidocaineinhibitionofthehyperpolarizationactivatedcyclicnucleotidegatedhcn1channel AT stephankwschwarz cationandvoltagedependenceoflidocaineinhibitionofthehyperpolarizationactivatedcyclicnucleotidegatedhcn1channel AT ericaaccili cationandvoltagedependenceoflidocaineinhibitionofthehyperpolarizationactivatedcyclicnucleotidegatedhcn1channel
_version_	1718384945662001152

Cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel

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